Prothrombotic Fibrin Clot Phenotype Is Associated With Recurrent Pulmonary Embolism After Discontinuation of Anticoagulant Therapy

Abstract

Objective— Pulmonary embolism (PE) is a life-threatening manifestation of venous thromboembolism with a high recurrence rate after anticoagulation cessation. Recently, we have reported that prothrombotic clot phenotype in venous thromboembolism patients is associated with an increased risk of recurrent deep-vein thrombosis. Approach and Results— We tested whether abnormal clot properties are predictive of recurrent PE. We investigated 156 consecutive white patients aged 18 to 65 years after the first-ever provoked or unprovoked PE (n=89), with or without deep-vein thrombosis. Plasma fibrin clot permeability (K s ), turbidity measurements, calibrated automated thrombography, and efficiency of fibrinolysis using clot lysis time, maximum D-dimer levels, and rate of increase in D-dimer levels were evaluated at ≥3 months of anticoagulant therapy, at least 4 weeks since the anticoagulation withdrawal. The primary end point was recurrent PE during a median follow-up of 50 months. Recurrent PE was diagnosed in 23 (14.7%; 5%/yr) patients. Recurrent PE was associated with formation of denser fibrin networks reflected by lower K s ( P =0.007) and impaired fibrinolysis, as evidenced by prolonged clot lysis time ( P =0.012) and reduced maximum rate of increase in D-dimer levels in the lysis assay ( P =0.004). Patients with recurrent PE had higher plasma D-dimer ( P <0.001) and thrombin peak ( P =0.007) compared with the remainder, whereas turbidity measurements and maximum D-dimer levels did not differ in the recurrence. Multivariate model showed that independent predictors of recurrent PE were female sex, unprovoked venous thromboembolism, higher plasma D-dimer, reduced K s , and reduced maximum rate of increase in D-dimer levels in the lysis assay (all P <0.05). Conclusions— Altered fibrin clot properties including formation of more compact clots displaying impaired susceptibility to lysis may predispose to recurrent PE.